The present invention pertains to the field of vaccination, and more particularly to the fields of antitumor and antiviral vaccination. The invention concerns the use of a native peptide in a medicinal composition, for selecting and/or boosting part of a CTL immune response which has been initiated by an optimized immunogenic peptide derived from said native peptide.
Cancer immunotherapy is intended to stimulate cytotoxic T lymphocytes (CTL) recognizing peptides derived from tumor antigens and presented at the tumor cell surface by HLA class 1 molecules. CTL targeted peptides can be dominant or cryptic (Moudgil and Sercarz 1994). Dominant peptides have high HLA affinity and are frequently presented by tumor cells. In contrast, cryptic peptides have low HLA affinity and are rarely presented by tumor cells. All cancer vaccines so far tested have targeted dominant peptides, with relatively little success (Slingluff, Yamshchikov et al. 2001; Knutson, Schiffman et al. 2002; Schaed, Klimek et al. 2002; Parkhurst, Riley et al. 2004; Vonderheide, Domchek et al. 2004). Studies using mouse models showed that this lack of efficacy is due to tolerance to tumor antigens, and especially to their dominant peptides (Cibotti, Kanellopoulos et al. 1992; Theobald, Biggs et al. 1997; Colella, Bullock et al., 2000; Hernandez, Lee et al. 2000; Grossmann, Davila et al. 2001; Gross, Graff-Dubois et al. 2004).
To circumvent this tolerance, vaccination with cryptic peptides was recently proposed. It was observed that in humanized mice, tolerance of cryptic peptides was weak or absent, and that cryptic peptides efficiently induced antitumoral immunity in vivo, providing their immunogenicity had been optimized (Tourdot, Scardino et al. 2000; Scardino, Gross et al. 2002; Gross, Graff-Dubois et al. 2004). A peptide sequence modification that optimizes immunogenicity of almost all low-affinity HLA-A*0201-restricted peptides tested was previously described (Tourdot, Scardino et al. 2000).
TERT572Y is an HLA-A*0201-associated optimized cryptic peptide derived from TERT, an antigen overexpressed by 85% of human tumors (Kim, Piatyszek et al. 1994). TERT572 is present in both human and murine TERT, and TERT572Y was able to induce antitumoral immunity in HLA-A*0201 transgenic mice, however no autoimmunity against normal TERT-expressing tissues was observed (Gross, Graff-Dubois et al. 2004). In vitro, TERT572Y stimulated antitumor CTLs from both healthy donors and prostate cancer patients. CTLs killed TERT-expressing tumor cells but not TERT-expressing normal cells (Hernandez, Garcia-Pons et al. 2002; Scardino, Gross et al. 2002).
However, in a similar vaccination approach, it has been reported that vaccination of melanoma patients with optimized gp100209M led to the amplification of T cells that were no longer able to recognize either the native gp100209 peptide or gp100-expressing melanoma cells (Clay, Custer et al. 1999).